Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival
Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival
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DOI：
10.1167/iovs.03-1380
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发表时间：
2004-08-01
影响因子：
4.4
通讯作者：
Streilein, JW
中科院分区：
文献类型：
--
作者：
Cursiefen, C;Cao, JT;Streilein, JW
目的.评估小鼠正常风险角膜移植后出血和淋巴管生成的发生和时间过程，并检测抑制这两个过程的药物策略是否能改善移植物的长期存活率。进行正常风险的同种异体（C57 BL/6至BALB/c）和同基因（BALB/c至BALB/c）角膜移植，并通过使用角膜平片的双重免疫荧光（以CD 31作为泛内皮和LYVE-1作为淋巴管内皮特异性标记）观察角膜移植术后出血和淋巴管生成的发生和时间过程。测试了设计用于消除VEGF-A的分子陷阱（VEGF陷阱（R1 R2）; 12.5 mg/kg）抑制角膜移植术后两个过程和促进长期移植物存活的能力（在手术当天和3、7和14天后腹膜内注射）。正常风险移植后，供体或宿主角膜均未立即检测到血管或淋巴管，但在移植后第3天，血管内皮细胞和淋巴管生成清晰可见。两种血管类型在同种异体移植后1周到达供体组织，在同基因移植后相似。术后早期VEGF-A的捕获显著减少了血管生成和淋巴管生成，并显著提高了移植物的长期存活率（78% vs. 40%; P < 0.05）。在术前无血管的受体床内，正常风险角膜移植术后同时存在VEGF-A依赖的血管生成和淋巴管生成。正常风险角膜移植后抑制出血和淋巴管生成（免疫反应的传入和传出臂）可改善移植物的长期存活率，建立术后早期出血和淋巴管生成作为移植物排斥的新风险因素，即使在低风险眼中。
PURPOSE. To evaluate the occurrence and time course of hem- and lymphangiogenesis after normal-risk corneal transplantation in the mouse model and to test whether pharmacologic strategies inhibiting both processes improve long-term graft survival.METHODS. Normal-risk allogeneic (C57BL/6 to BALB/c) and syngeneic (BALB/c to BALB/c) corneal transplantations were performed and occurrence and time course of hem- and lymphangiogenesis after keratoplasty was observed, by using double immunofluorescence of corneal flatmounts ( with CD31 as a panendothelial and LYVE-1 as a lymphatic vascular endothelium -specific marker). A molecular trap designed to eliminate VEGF-A (VEGF Trap(R1R2); 12.5 mg/kg) was tested for its ability to inhibit both processes after keratoplasty and to promote long-term graft survival ( intraperitoneal injections on the day of surgery and 3, 7, and 14 days later).RESULTS. No blood or lymph vessels were detectable immediately after normal-risk transplantation in either donor or host cornea, but hem- and lymphangiogenesis were clearly visible at day 3 after transplantation. Both vessel types reached donor tissue at 1 week after allografting and similarly after syngeneic grafting. Early postoperative trapping of VEGF-A significantly reduced both hem- and lymphangiogenesis and significantly improved long-term graft survival (78% vs. 40%; P < 0.05).CONCLUSIONS. There is concurrent, VEGF-A-dependent hem- and lymphangiogenesis after normal-risk keratoplasty within the preoperatively avascular recipient bed. Inhibition of hem- and lymphangiogenesis ( afferent and efferent arm of an immune response) after normal-risk corneal transplantation improves long-term graft survival, establishing early postoperative hem- and lymphangiogenesis as novel risk factors for graft rejection even in low-risk eyes.